Search Results (243)

Background/Objectives: Obesity is a global health emergency with a complex etiology, in which monogenic forms, although rare, are significantly underdiagnosed. In our clinical setting, first-tier genetic screening panels targeting LEP, LEPR, BDNF, FTO, and MC4R often fail to identify a causative variant, leaving a significant diagnostic gap. This study aimed to assess the prevalence of variants in other critical genes of the melanocortin pathway to improve diagnostic yield. Methods: We analyzed 88 patients with non-syndromic obesity (Body Mass Index, BMI > 30 kg/m²), who were first screened for our standard obesity-related genes. In those testing negative, we expanded the analysis to include the MC3R and POMC genes. In silico bioinformatic tools were used to predict the functional consequences of identified variants on protein structure and splicing. Results: We found several variants in POMC, specifically within the regions coding for alpha-, beta-, and gamma-MSH peptides. A bioinformatic analysis suggests that these variants disrupt the melanocortin signaling pathway, likely contributing to an intermediate susceptibility phenotype in our adult cohort. Additionally, a clinical follow-up of a patient carrying the rare BDNF p.Thr2Ile variant revealed a suboptimal response to high-dose tirzepatide treatment (9% weight loss over 72 weeks), notably inferior to the average response observed in clinical trials. Conclusions: Our findings demonstrate that expanding first-level routine testing to include POMC and MC3R is essential to maximize diagnostic yield and improve clinical management. Full article

Human diseases are complex and arise from the coordinated action of multiple genes and their protein products. Genes’ behaviors extend beyond genetic variants, mutations, and differential expressions. Their coordinated activity across biological scales (molecules, cells, tissues, organs) produces emergent behaviors that shape health and disease. These emergent behaviors span time and space and are often hard to measure directly from observation when using standard experimental measurements. Yet these “hidden” or latent gene characteristics can be powerful drivers of disease. We propose a Mini-Galaxy Model (MGM), a systems-level AI-driven network framework that models cells as “mini-galaxies” composed of multilayered biological information, with each layer encoding a different dimension of genes’ behavior. Here, we delineate a strategy on how to construct and compare MGMs across health and disease and map their etiological relatedness. We also operationalize the MGM as a discovery platform for translational medicine, offering modules to allow target prioritization and editing. By reframing human diseases as the result of emergent behavior of multilayered multimode biological networks and their perturbations, the MGM yields actionable rules to streamline biomarker discovery, guide target selection and enable rational design of combinatorial interventions, and accelerate drug repurposing. Full article

Background/Objectives: Early-onset high myopia (eoHM), defined as high myopia manifesting before 10 years of age, is largely attributed to genetic defects. This study aimed to investigate the genetic underpinnings of eoHM in a cohort of Chinese patients. Methods: We recruited 64 Chinese patients with eoHM. Comprehensive clinical evaluations were performed, and whole exome sequencing (WES) was conducted to identify potential pathogenic variants. The genetic findings were analyzed and correlated with the clinical phenotypes. Results: A total of 64 unrelated Chinese patients with suspected early-onset high myopia were initially recruited. Following whole exome sequencing (WES) and variant annotation, final 37 patients with variants in known myopia-associated genes were included in the analytical cohort. The mean age of onset for the cohort was 5 years (IQR, 4–7), with a mean spherical equivalent refraction of −7 D (IQR, (−8)–(−6)). Genetic analysis revealed variants in 28 known myopia-associated genes. We identified pathogenic or likely pathogenic variants in 11 of the 37 patients (29.7%, 95%CI: 0.1737–0.4590), while the overall diagnostic yield was 17.2% (11/64, 95%CI: 0.0970–0.2839) in initial 64 recruited patients. These genes included seven well-established eoHM-related genes, such as ARR3, CACNA1F, P4HA2, TRPM1, COL11A1, COL2A1, and PAX6. Additionally, variants of uncertain significance (VUS) in seven other candidate genes were detected in patients with eoHM. Conclusions: Our findings expand the genetic spectrum of eoHM and reinforce the critical role of genetic testing in its etiological diagnosis and clinical management. Observed patterns of genotype–phenotype associations are descriptive and should be considered hypothesis-generating, requiring validation in larger cohorts. Additionally, we identify several candidate genes that may serve as prospective biomarkers, though these findings require validation in larger cohorts and functional studies. Full article

Background: The contribution of intronic variants to the etiology of Mendelian diseases is still underrecognized, impacting the diagnostic yield. Whole genome sequencing (WGS) detects intronic variants, but besides canonical splice-sites, intronic variants are frequently excluded from the interpretation step or are classified as variants of uncertain significance (VUS). In fact, assessing their clinical significance often requires validation via RNA-sequencing (RNA-seq) or in vitro studies. Methods: We studied a 31-year-old patient with spinocerebellar ataxia who lacked a molecular diagnosis after WGS analysis. We applied the Detection of RNA Outliers Pipeline (DROP) to analyze RNA-seq data from patient fibroblasts. DROP integrates OUTRIDER and FRASER 2.0 algorithms designed to identify aberrant gene expression and splicing, respectively. Results: DROP identified differential expression and aberrant splicing of SNX14. Retrospective WGS data analysis revealed a homozygous NM_153816.6(SNX14): c.867+288A>G deep intronic variant, which caused pseudo-exon activation and reduced transcript levels. Biallelic loss-of-function variants in SNX14 cause autosomal recessive spinocerebellar ataxia type 20 (SCAR20; OMIM 616354), consistent with the clinical presentation of this case. Conclusions: We identify a deep intronic SNX14 variant as the genetic basis of SCAR20. We demonstrate the utility of RNA-seq to increase the diagnostic yield by identifying and resolving the pathogenicity of deep intronic variants. Defining aberrant splicing events is therapeutically relevant, as these mechanisms are targets for antisense oligonucleotide (ASO) based interventions. Full article

Helicobacter pylori (H. pylori) is the primary etiological agent for chronic gastritis, peptic ulcers, and gastric adenocarcinoma. The alarming rise in multidrug-resistant (MDR) strains, particularly against clarithromycin (CLR), metronidazole (MNZ), and levofloxacin (LVX), has severely compromised standard therapies. Thus, there is an urgent clinical need for novel antimicrobial agents that operate through distinct mechanisms to bypass resistance pathways and mitigate gastric cancer risk. We designed and synthesized a series of antimicrobial peptides, focusing on the proteolytically stable all-D-amino acid enantiomer, DT7-3, derived from a probiotic-sourced template. Minimum inhibitory concentrations (MICs) were determined against standard strains and 11 clinical MDR isolates via the broth microdilution method. Antimicrobial mechanisms were elucidated using scanning electron microscopy (SEM) for morphology, fluorescence-based assays for anti-adhesion activity, and real-time qPCR to quantify virulence gene expression (babA, ureA, and vacA). Biocompatibility was assessed using defibrinated sheep erythrocytes, gastric epithelial cells (GES-1), and representative beneficial gut microbiota. Analysis of the clinical isolates revealed resistance rates of 63.6% for CLR/LVX and 81.8% for MNZ, with 54.5% identified as MDR. DT7-3 exhibited superior potency (MIC 1–32 µg/mL) against all strains, significantly outperforming its L-enantiomer counterparts. Mechanistic studies unveiled a “triple-hit” mechanism: (1) rapid membrane disruption; (2) potent inhibition of bacterial adhesion to host cells (~60% reduction at 0.5 × MIC); (3) significant downregulation of critical virulence factors (babA, ureA, and vacA). Furthermore, DT7-3 showed an excellent safety profile, with negligible hemolysis (<5% at 32 µg/mL) and minimal cytotoxicity toward GES-1 cells, yielding a high selectivity index (SI, MHC/MIC) > 32 relative to mammalian cells. Crucially, DT7-3 showed high selectivity for the pathogen over beneficial gut microbiota (MIC > 128 µg/mL, SI > 16). Crucially, DT7-3 maintained potent bactericidal activity (MIC ≤ 16 µg/mL) even under cholesterol-enriched conditions. The engineered D-peptide DT7-3 is a potent candidate for combating MDR H. pylori. Its multifaceted mechanism, targeting bacterial viability while suppressing core virulence factors, positions it as a robust lead compound for next-generation eradication therapies aimed at reducing the burden of H. pylori-associated diseases. Full article

Objective: To evaluate the diagnostic and prognostic utility of the hemoglobin–albumin–lymphocyte–platelet (HALP) score and several systemic inflammatory indices derived from routine blood parameters—including the systemic immune-inflammation index (SII), platelet-to-lymphocyte ratio (PLR), pan-immune inflammation value (PIV), and systemic inflammatory response index (SIRI)—for pathogen differentiation and clinical assessment in culture-proven late-onset neonatal sepsis (LOS). Methods: A retrospective analysis was conducted on a cohort of 150 neonates with culture-proven LOS. Systemic inflammatory indices were calculated at baseline (first week of life) and at the time of septic insult. The discriminative power of these indices was assessed via ROC curve analysis, with optimal cut-off points determined by the Youden Index. Risk stratification was performed using Odds Ratio (OR) modeling with 95% Confidence Intervals (CIs) to evaluate the predictive strength of each marker according to its respective threshold. Results: Diagnosis-phase assessments identified SII as the premier discriminator for microbiological etiology (AUC = 0.869; OR = 44.57), outperforming PLR and PIV. Although HALP demonstrated moderate efficacy in distinguishing pathogens, it lacked prognostic value regarding mortality. Conversely, SIRI displayed limited clinical utility, yielding the lowest predictive performance in our cohort. Conclusions: In neonatal sepsis, the HALP score provided additional clinical information when compared with several hematological inflammatory indices. Although HALP was not associated with mortality, prospective multicenter studies are needed to clarify the role of these cost-effective markers in pathogen differentiation and clinical assessment of LOS. Full article

Background: Freezing of gait (FoG) is a common symptom of Parkinson’s disease, especially in its later stages of progression. Characterized by involuntary stopping during normal gait patterns, FoG greatly increases fall risk, reducing quality of life. Given the complex presentation and etiology of FoG, current treatments have proven ineffective in managing episodes. In recent years, machine learning algorithms have been leveraged to derive actionable clinical insights from biomedical datasets. As a manifestation of neuromechanical dysfunction, impending FoG episodes may be characterized through data collected by wearable devices and sensors. Objective: This scoping review evaluates the current landscape of machine and deep learning-derived biomarkers to enhance the personalized management of FoG. Methods: This scoping review was conducted using established methodological frameworks for scoping reviews and is reported in accordance using the PRISMA-ScR checklist. Three databases were queried, with screening yielding 60 studies. Results: Thirty-nine papers reported on deep learning techniques, with the most common architectures being convolutional neural networks and long short-term memory models. Conclusions: Inertial measurement units, which can be worn on various locations, may be a promising modality for practical implementation. To generate closed-loop FoG therapies, algorithms can be integrated into real-time systems like robotic exoskeletons or adaptive deep brain stimulation. Future work in generating datasets from ambulatory devices, as well as distributed computing strategies, may lead to real-time FoG management. Full article

Lichen planus (LP) is a chronic immune-mediated inflammatory disease of unknown etiology affecting the skin and mucous membranes and is frequently associated with comorbid conditions, although data from Swedish populations remain limited. This retrospective population-based case–control study included all registered citizens in Region Jönköping, Sweden, between 2013 and 2022, to examine comorbidities, estimate prevalence and incidence, assess diagnostic validity of ICD-10 coding (L43), and evaluate treatment patterns. Incidence and prevalence were calculated, demographic and treatment characteristics were described, and diagnostic validity was assessed through independent medical record review of 70 randomly selected cases to determine positive predictive value (PPV). Associations between LP and predefined comorbidities were analyzed using binomial logistic regression adjusted for age and sex. Among 361,812 individuals, prevalence was 235.5 and incidence 19.6 per 100,000 inhabitants. The PPV of the LP diagnosis was 78.6%, yielding an adjusted prevalence of 184.9 per 100,000 inhabitants. Over one third of prevalent patients received topical therapy, primarily corticosteroids. LP was significantly associated with thyroid, malignant, metabolic, and autoimmune conditions. LP is relatively uncommon, ICD-10 coding shows acceptable validity, and its association with clinically relevant comorbidities highlights the need for comprehensive patient assessment. Full article

Background/Objectives: The optimal surgical timing for rotator cuff tears (RCTs) remains controversial, particularly regarding how tear etiology influences the final functional recovery. This study aimed to compare the clinical outcomes of early versus delayed arthroscopic repair stratified by etiology, providing evidence for etiology-specific surgical timing. Methods: A retrospective cohort study was conducted on 183 patients who underwent arthroscopic rotator cuff repair for isolated full-thickness supraspinatus tears. Patients were stratified into traumatic (n = 74) and degenerative (n = 109) groups based on etiology. They were further divided into early-repair and delayed-repair subgroups based on symptom duration (traumatic cut-off: 3 months; degenerative cut-off: 6 months). Clinical outcomes were assessed preoperatively and at the final follow-up using the Visual Analog Scale (VAS) for pain, American Shoulder and Elbow Surgeons (ASES) score, University of California at Los Angeles (UCLA) score, and range of motion. Complications, including retear rates and stiffness, were recorded. Results: In the traumatic group, early repair yielded significantly better postoperative pain relief (VAS) and higher functional scores (ASES and UCLA) compared to delayed repair. Notably, the delayed traumatic group exhibited a significantly higher retear rate compared to the early group (16.7% vs. 2.6%; p = 0.039). Conversely, in the degenerative group, comparisons between early and delayed repair revealed no significant differences in the final functional scores, pain levels, or complication rates (p > 0.05). Conclusions: Surgical timing significantly impacts outcomes in traumatic RCTs, where early repair is critical to optimize functional recovery and minimize retear risks. In contrast, delayed arthroscopic repair for degenerative tears yielded comparable outcomes to early repair, suggesting that an initial trial of conservative management is safe and does not compromise final surgical outcomes. Full article

Introduction: Recombinant human deoxyribonuclease I (rhDNase) cleaves DNA in mucus, facilitating increased mucociliary clearance of purulent sputum. In cystic fibrosis (CF), rhDNase improves pulmonary function and decreases exacerbations. Conversely, rhDNase use in non-CF bronchiectasis (NCFB) patients has not yielded similarly effective results. We explored the safety and feasibility of rhDNase in patients with bronchiectasis due to primary ciliary dyskinesia (PCD). Methods: In this real-life pilot study, patients with PCD received rhDNase to treat viscous mucus. We compared pulmonary function tests and pulmonary exacerbations for these patients over six months of use of rhDNase. Results: Eight PCD patients with symptomatic bronchiectasis commenced use of rhDNase at variable dosing (ranging from at least twice weekly to a full 2.5 mg dose daily). Over a six-month period, pulmonary function tests, as measured by mean FVC and FEV₁, remained relatively stable compared to prior to commencing rhDNase. Mean pulmonary exacerbations decreased from 3.1 to 2.3 in the six-month period after commencing rhDNase, as compared to the six-month period prior to rhDNase. Conclusions: Use of rhDNase in PCD patients was safe and did not adversely impact lung function or increase pulmonary exacerbations, in contrast to earlier trial results in NCFB patients with heterogeneous etiologies. Further clinical data is required to identify the population of PCD patients who can benefit from rhDNase, as well as the appropriate dosing and timing. Full article

Background: Ureaplasma spp. and Mycoplasma hominis are urogenital pathogens that may be missed by routine culture, particularly in patients with genitourinary symptoms in whom conventional methods fail to identify an etiologic agent. Limited routine implementation of targeted diagnostics and antimicrobial susceptibility testing (AST) for these organisms may contribute to diagnostic uncertainty and treatment failure. Methods: Seventy-five midstream urine samples submitted for suspected urinary tract infection and positive for Ureaplasma spp. according to a q-PCR urinary panel (Bioeksen, İstanbul, Türkiye) were tested the same day with MYCOPLASMA IST3 (bioMérieux, Marcy-l’Étoile, France) to assess growth and antimicrobial susceptibility. Results: q-PCR detected U. parvum in 54/75 (72%), U. urealyticum in 15/75 (20%), and both species in 6/75 (8%); M. hominis was not included in the PCR panel. MYCOPLASMA IST3 showed growth in 70/75 samples (positive percent agreement, 93.33%), while 5/75 (discordance, 6.66%) showed no growth. Among culture-positive samples, 57/70 (81.42%) yielded Ureaplasma spp. alone, and 13/70 (18.58%) yielded Ureaplasma spp. together with M. hominis. Resistance to levofloxacin and tetracycline was observed in 15.7% and 12.9% of Ureaplasma spp. isolates, respectively; resistance to moxifloxacin, erythromycin, and telithromycin was observed in 2.9% of isolates for each agent. In M. hominis isolates, no resistance to levofloxacin, moxifloxacin, or tetracycline was observed, whereas clindamycin resistance was observed in 7.7% of isolates. Conclusions: In addition to intrinsic resistance, acquired antimicrobial resistance in Ureaplasma and Mycoplasma species appears to be increasing; therefore, treatment decisions should be guided by AST whenever feasible. Clinical laboratories should implement appropriate diagnostic methods for these organisms and perform susceptibility testing when indicated to support clinical decision making and optimize antimicrobial selection. Full article

Background: Vertigo and dizziness in children represent diagnostically challenging conditions with heterogeneous etiologies. At initial presentation, a substantial proportion of pediatric patients remain without a definitive etiological diagnosis. Evidence on the impact of longitudinal follow-up on etiological classification in pediatric vertigo is limited. Methods: This observational cohort study uses prospectively collected clinical data. Children aged 1–17 years who presented to a tertiary ENT clinic with vertigo and/or dizziness between 2015 and 2020 were systematically enrolled and followed. The present study represents a retrospective revision of a previously published cohort of 257 children. In 2025, extended follow-up data were reviewed to reassess etiological classification using the same diagnostic categories as in the original analysis. Descriptive statistics were applied to compare etiological distributions at initial evaluation and after follow-up revision. Results: After data revision, the proportion of children with unclassified etiology decreased from 44% to 10%. Central etiologies accounted for 35% of cases, peripheral vestibular disorders for 18%, hemodynamic causes for 16%, psychogenic etiologies for 10%, and other specific causes for 7%. Follow-up duration ranged from 0 to 132 months (mean 17.6 months; median 4.5 months). Diagnostic investigations were frequently performed; however, the etiological yield of certain tests, particularly cranial computed tomography, was low. Conclusions: Extended follow-up significantly improves etiological classification in children with vertigo and dizziness, demonstrating that diagnostic uncertainty at initial presentation often reflects evolving clinical phenotypes rather than the absence of an underlying disorder. A longitudinal, clinically guided, and multidisciplinary approach is essential to enhance diagnostic accuracy and optimize the use of diagnostic investigations in pediatric vertigo. Full article

Yam end black disease (YEBD) is a devastating soil-borne disease that severely compromises the yield of Chinese yam (Dioscorea opposita Thunb.). Despite its agricultural importance, the etiological agents and molecular mechanisms underlying YEBD remain poorly understood. In this study, we employed an integrated multi-omics approach, combining transcriptomics and microbiome analysis, to dissect the host responses and microbial shifts associated with YEBD. De novo transcriptome assembly revealed significant enrichment of differentially expressed genes involved in polyamine metabolism and hormone signaling pathways. Microbiome profiling identified a substantial increase in nematodes (Meloidogyne spp.) in diseased samples, which correlated negatively with the beneficial fungus Cladosporium. Bacterial community analysis showed an increase in Proteobacteria and Bacteroidetes and a decrease in Actinobacteria and Firmicutes in YEBD-affected roots. Notably, the rhizosphere microbiome was less affected than the endophytic community, suggesting that internal microbial dysbiosis plays a critical role in disease progression. These findings provide new insights into the interactions among yam, nematodes, and microbes, offering potential strategies for biocontrol and disease management. Full article

Primary hyperparathyroidism (PHPT) in the pediatric population is a rare but clinically important endocrine disorder that poses significant diagnostic and therapeutic challenges. In contrast to adult PHPT, which is often detected incidentally, pediatric patients are frequently symptomatic at diagnosis, with manifestations reflecting prolonged exposure to hypercalcemia and elevated parathyroid hormone levels. Neonatal forms, particularly neonatal severe hyperparathyroidism, represent life-threatening conditions requiring prompt biochemical recognition and urgent intervention. The heterogeneity of clinical presentation and the rarity of the disease contribute to delayed diagnosis and increased risk of end-organ complications. Although hereditary syndromes are proportionally more frequent in children than in adults, sporadic PHPT remains the most common etiology in pediatric patients and is typically caused by a single parathyroid adenoma. Genetically determined forms, including multiple endocrine neoplasia syndromes, hyperparathyroidism–jaw tumor syndrome, and calcium-sensing receptor-related disorders, are often associated with multiglandular disease, earlier onset, and a higher risk of persistence or recurrence. Biochemical confirmation remains the cornerstone of PHPT diagnosis, while diagnostic imaging plays an important role in preoperative localization and surgical planning. High-resolution cervical ultrasound is the preferred first-line imaging modality in pediatric patients due to its excellent diagnostic performance and absence of ionizing radiation. Functional and advanced cross-sectional imaging techniques should be applied in a stepwise manner in selected cases with inconclusive first-line imaging or suspected ectopic disease, balancing diagnostic yield against radiation exposure. Surgical management remains the definitive treatment for pediatric PHPT. The extent of surgery is determined by disease etiology, localization findings, and intraoperative assessment, with focused parathyroidectomy favored in sporadic single-gland disease and more extensive approaches required in genetically determined forms. This review highlights a structured diagnostic and therapeutic pathway for pediatric PHPT, emphasizing the integration of biochemical testing, imaging strategies, genetic evaluation, and individualized surgical management to optimize outcomes and reduce long-term morbidity. Full article

Prosthetic-valve endocarditis (PVE) represents one of the most serious forms of infective endocarditis, marked by high mortality and considerable management complexity. The 2023 European Society of Cardiology (ESC) Guidelines emphasise the diagnostic centrality of repeatedly positive blood cultures. Nonetheless, a significant area of uncertainty remains regarding the diagnostic and prognostic value of cultures from explanted prosthetic valves—particularly in centres lacking access to molecular diagnostics. Case Presentation: We report a case of prosthetic-valve endocarditis on a bioprosthesis, in which repeated blood-culture sets yielded Streptococcus acidominimus, whereas culture of the explanted valve revealed Staphylococcus warnerii. The patient received six weeks of intravenous vancomycin, with treatment tailored according to the patient’s clinical and laboratory parameters and in alignment with international endocarditis guidelines, obtaining a clear clinical and laboratory improvement. Discussion: The literature reports that discordance between blood-culture and valve-culture results in infective endocarditis may range from approximately 10% to 29%, attributable to contamination, biofilm formation or polymicrobial infection. In our case, management guided by the microorganism repeatedly isolated from blood cultures proved effective and aligned with the 2023 European Society of Cardiology (ESC) guidelines. The case underlines the importance of a multidisciplinary team and an integrated interpretation of microbiological, clinical and surgical data. Conclusions: Infective endocarditis with discordant isolates presents a complex diagnostic challenge. The etiological diagnosis must rely primarily on the results of blood cultures, whereas valve culture plays a complementary role—useful more for prognostic stratification than for initial diagnostic purposes. A multidisciplinary approach and a critical interpretation of microbiological findings are essential to optimise therapeutic management and improve patient outcomes. Full article